The invention is in the field of therapeutic compositions and methods, particularly chemotherapy of cancer using ginsenosides.
Panax ginseng has served as an important component of traditional Chinese medicine for thousands of years. Recently, attention has been focused on the pharmacological activity of various compounds found in ginseng. As early as 1854, a saponin fraction was isolated from American ginseng, Panax quinquefolium L. In the late 1950s, saponin fractions collectively called ginsenosides were isolated from ginseng and structurally characterized. Ginsenosides are composed of a sugar portion (glycon) and a non-sugar portion (aglycon). Individual, isolated ginsenosides are commonly named according to the order of the Rf value of the compound on thin layer chromatograms (for example, Ra, Rb1, Rb2). By about the mid 1980s, a group of Rh ginsenosides were isolated. To date, at least four compounds, Rh1 to Rh4 have been isolated in the Rh group, each differentiated by the position of a glycon. Rh2 is a ginseng saponin with a dammarane skeleton that may be isolated from the root of Panax ginseng C. A. Meyer. Rh2 has the following formula, in which xe2x80x9cGlcxe2x80x9d is the glycon (glucose): 
Rh2 may be available commercially, for example from Pegasus Pharmaceuticals Inc. (Vancouver, British Columbia, Canada). A wide variety of physiological effects have been attributed to ginsenosides, including Rh2, and the mechanism of action of these compounds and the range of potential therapeutic activities of each of the compounds remains uncertain.
Mitoxantrone is an antineoplastic agent which may be prepared as a synthetic antracenedione derivative of the anthraquinone dye ametantrone. Mitoxantrone has the following formula: 
Mitoxantrone has reportedly been used in the treatment of a variety of malignant diseases, including acute non-lymphcytic leukaemia, advanced breast cancer and prostate cancer (see Wiseman and Spencer, Drugs and Aging, 1997 June 10(6): 473). Mitoxantrone is available commercially, and its preparation is for example described in U.S. Pat. No. 4,197,249; incorporated herein by reference.
Paclitaxel is a derivatized diterpenoid which may be obtained from the bark of the Pacific Yew and other natural sources (Taxus brevifolia, see Wani et al., J. Am. Chem. Soc. 93:2325, 1971; and Stierle et al., Science 60:214-216, 1993). Therapeutically, particularly in cancer therapy, paclitaxel is thought to act to stabilize microtubular structures by binding tubulin. As used herein, the word xe2x80x9cpaclitaxelxe2x80x9d may include analogues, derivatives and conjugates of the naturally-occurring molecule, such as TAXOL(trademark), TAXOTERE(trademark), 10-desacetyl analogues of paclitaxel, 3xe2x80x2N-desbenzoyl-3xe2x80x2N-t-butoxy carbonyl analogues of paclitaxel, paclitaxel-PEG, paclitaxel-dextran, or paclitaxel-xylos. Paclitaxel may be prepared utilizing a variety of techniques (see WO 94/07882, WO 94/07881, WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076, U.S. Pat. Nos. 5,294,637, 5,283,253, 5,279,949, 5,274,137, 5,202,448, 5,200,534, 5,229,529, and EP 590267), or obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Mo.
Cisplatin is an inorganic compound possessing a platinum element. 
Cisplatin (cis-diaminedichloroplatinum (II)) has been used as a chemotherapeutic agent for many years since discovery of its antitumour activity (Rosenberg et al., Nature, 205:698, 1965; Rosenberg et al., Nature 222:385, 1969; U.S. Pat. No. 4,177,263). The mechanism of action of cisplatin in cancer therapy is believed to be through its ability to bind to DNA to interfere with repair mechanisms, causing cell death. Cisplatin has been reported to be effective in the treatment of a variety of cancers, most significantly in the treatment of ovarian and testicular cancer. Cisplatin is available commerically, for example, from Bristol-Myers Squibb Company under the commercial name PLATINOL(trademark).
Cancerous tumors that have responded well initially to a particular drug or drugs, may later develop a tolerance to the drug(s) and cease responding, a phenomenon known as drug resistance. Multidrug resistance is generally characterized by cross-resistance of a disease such as cancer to more than one functionally or structurally unrelated drugs. Multidrug resistance may be caused by a number of mechanisms. For example, multidrug resistance may be mediated by a protein that is variously called multidrug-resistance 1 protein (MDR1), pleiotropic-glycoprotein (P-glycoprotein), Pgp or P170, referred to herein as xe2x80x9cP-glycoproteinxe2x80x9d. P-glycoprotein is thought to be endogenous in cell membranes in certain drug resistant cells, multidrug resistant tumor cells, gastrointestinal tract cells, and the endothelial cells that form the blood brain barrier, where P-glycoprotein is thought to act as an efflux pump for the cell. Certain substances, including treatment drugs for various diseases, may be pumped out of the cell by the P-glycoprotein prior to having a therapeutic effect on the cell. There is accordingly a need for therapeutic approaches that may be used to counteract drug resistance, particularly multidrug resistance mediated by P-glycoprotein in cancer.
In one aspect, the invention provides methods inhibiting the multiplication of cancer cells, and methods of treating cancer in patients in need of such treatment, comprising administering to such patients therapeutically and synergistically effective amounts of Rh2 in combination with a chemotherapeutic selected from the group consisting of paclitaxel and mitoxantrone. The cancer cells to be treated may be multidrug resistant. The cancer cells may for example be prostate cancer cells or breast cancer cells.
In alternative aspects, the invention provides for the use of Rh2 in combination with a chemotherapeutic selected from the group consisting of paclitaxel and mitoxantrone to synergistically inhibit the multiplication of cancer cells, or to formulate a medicament for inhibiting the multiplication of cancer cells synergistically. The cancer cells to be treated may be multidrug resistant. The cancer cells may for example be prostate cancer cells or breast cancer cells.
In alternative aspects, the invention provides for the use of Rh2 to render non-P-glycoprotein multidrug resistant cancer cells (cancer cells that do not express P-glycoprotein) sensitive to a chemotherapeutic. In such embodiments, a chemotherapeutic may for example be used with Rh2 to treat a patient at a concentration or dosage at which the chemotherapeutic alone would otherwise not be effective in said non-P-glycoprotein multidrug resistant cancer cells. The chemotherapeutic may for example be paclitaxel, mitoxantrone, or cisplatin. The cancer cells may, for example, be prostate cancer cells or breast cancer cells.
In alternative aspects, the invention provides a pharmaceutical composition for the treatment of cancer, in patients in need of such treatment, comprising: a pharmaceutically acceptable carrier; and, therapeutically and synergistically effective amounts of Rh2 and a chemotherapeutic selected from the group consisting of paclitaxel and mitoxantrone.